ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.266T>A (p.Ile89Asn) (rs121964855)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211864 SCV000060219 pathogenic Hypertrophic cardiomyopathy 2015-03-31 criteria provided, single submitter clinical testing The p.Ile79Asn variant in TNNT2 has been reported in 3 probands with HCM and seg regated with disease in >15 affected relatives from two families (Thierfelder 19 94 and Watkins 1995, Varnava 1999, Menon 2008). It was absent from large populat ion studies. In vitro functional studies and animal models suggest that the p.Il e79Asn variant may impact protein function (Yanaga 1999, Miller 2001, Knollmann 2001). In summary, this variant meets our criteria to be classified as pathogeni c for HCM in an autosomal dominant manner ( edicine/LMM) based upon segregation studies, absence from controls, and function al evidence.
GeneDx RCV000159272 SCV000209218 pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing p.Ile79Asn (ATC>AAC): c.236 T>A in exon 8 of the TNNT2 gene (NM_001001430.1). The I79N mutation in the TNNT2 gene has been reported in association with HCM (Thierfelder L et al., 1994; Watkins H et al., 1995; Varnava A et al., 2001). Thierfelder et al. reported the I79N mutation in five individuals with HCM in one family, and did not observe the mutation in seven unaffected individuals in the family, or in 200 normal chromosomes. In a follow up study of the family previously analyzed, Watkins et al. reported the I79N mutation was present in up to nine individuals in the family, four of whom suffered a sudden death. One of the reported sudden death cases was a 16-year old male with the I79N mutation who had normal findings on clinical evaluation. Varnava et al. reported the I79N mutation in one case of sudden cardiac death, and did not observe the mutation in 180 chromosomes from control subjects. I79N represents a non-conservative amino acid change, replacing a nonpolar Isoleucine with a polar Asparagine. In addition, I79N affects a residue that is conserved in all known vertebrate troponin T sequences (Thierfelder L et al., 1994). I79N was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, I79N in the TNNT2 gene is interpreted as a disease-causing mutation. Hereditary hypertrophic cardiomyopathy (HCM) is primarily an autosomal dominant disease characterized by myocardial hypertrophy in the absence of other cardiac or systemic causes. HCM is most frequently caused by mutations in genes coding for sarcomeric proteins in the cardiac muscle leading to myocyte disarray, a hallmark feature of HCM. Less commonly, ventricular hypertrophy is a presenting feature of genetic systemic disorders, such as Danon disease, Fabry disease, or mitochondrial cardiomyopathy. HCM has a variable clinical presentation; including palpitations, chest pain, heart failure, syncope, or sudden death, although some individuals may be asymptomatic (Marian A et al., 1995; Maron B, 2002). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV000684789 SCV000285647 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 79 of the TNNT2 protein (p.Ile79Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (rs121964855, ExAC no frequency). This variant has been reported to segregate with familial cardiomyopathy in several families (PMID: 8205619, 18651846) has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 26914223). ClinVar contains an entry for this variant (Variation ID: 12408). Experimental studies have shown that this missense change has a significant effect on calcium sensitivity (PMID: 10085122, 10617660, 23663841). In addition, transgenic mice containing this variant have significantly abnormal cardiac contractile function (PMID: 11060291, 11113119, 21683708). In summary, this variant is absent from population databases, has been shown to segregate with disease, and has a deleterious effect on protein function., For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000243910 SCV000319765 pathogenic Cardiovascular phenotype 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Strong segregation with disease (lod >3 = >10 meioses)
Blueprint Genetics RCV000159272 SCV000927479 pathogenic not provided 2017-11-23 criteria provided, single submitter clinical testing
OMIM RCV000013217 SCV000033464 pathogenic Familial hypertrophic cardiomyopathy 2 2008-11-01 no assertion criteria provided literature only
OMIM RCV000013218 SCV000033465 pathogenic Left ventricular noncompaction 6 2008-11-01 no assertion criteria provided literature only
OMIM RCV000013219 SCV000033466 pathogenic Familial restrictive cardiomyopathy 3 2008-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159272 SCV000280514 pathogenic not provided 2014-07-23 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ile79Asn (c.236T>A) in the TNNT2 gene. This variant has been reported in at least one family with HCM and a high burden of sudden death, one family with a range of cardiomyopathy phenotypes, and in one case of sudden cardiac death. Strong segregation data has been reported in both cardiomyopathy kindreds. Thierfelder et al (1994) and Watkins et al (1995) reported a family with 9 affected family members who all had this variant; four of these individuals suffered a sudden cardiac death. One of the individuals who died suddenly and had the variant was a 16 year old male who had normal clinical findings. Varnava et al (2001) reported the variant in a male who died suddenly at 16 years of age and had evidence of HCM on autopsy. They did not provide detailed phenotypic information about that individual. Menon et al (2008) reported a family with RCM, HCM, and DCM; all nine affected family members carried the p.Ile79Asn variant. Disease-associated variants have been reported in neighboring codons (p.Phe77Leu and p.Gly83Lys), indicating the functional significance of this region in the TNNT2 gene. This is a non conservative amino acid change with a nonpolar Isoleucine being replaced with a polar Asparagine. Isoleucine is completely conserved at position 79 in the cardiac troponin T sequence across all vertebrates. Transgenic mice with this variant do not develop cardiac hypertrophy, even with chronic exercise, however they do show increased calcium sensitivity of the ATPase activity and force development in cardiac myofilaments (Miller et al 2001). Knollman et al (2001) further characterized transgenic mice, concluding that the increased myofilament calcium sensitivity increases baseline contractility but leads to cardiac dysfunction during inotropic stimulation. Rust et al (1999) studied the variant in single adult cardiomyocytes and observed impaired expression of the mutant protein and a disabling of cardiac contraction in the submaximal range of myoplasmic calcium concentrations. Lin et al (1996) studied the equivalent variant in rats and found 50% faster thin filament movement over a surface coated with heavy meromyosin. The variant has also been found to decrease the calcium sensitivity of force production and increase the unloaded shortening velocity (Sweeney et al 1998). Palm et al (2001) found that p.Ile79Asn does not affect tropomyosin binding while variants in resides 92-110 do. Some authors have suggested that this variant and other variants in TNNT2 confer a greater risk of sudden cardiac death with less or even no hypertrophy (Watkins et al 1995; Varnava et al 2001). Certainly the family reported by Thierfelder et al (1994) and then Watkins et al (1995) had multiple cases of sudden death, several with little or no hypertrophy. However, the family reported by Menon et al (2008) had no cases of sudden death or ventricular arrhythmias. In total the variant has not been seen in ~6890 published controls and individuals from publicly available population datasets. There is no variation at codon 79 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of January 30th, 2013). The variant is listed in dbSNP and 1000 genomes but ony in reference to the OMIM entry (rs121964855) (as of January 30th, 2013). The variant was not observed in the following published control samples: Thierfelder et al (1994) did not observe the variant in 100 presumably healthy controls whose race is unspecified. Varnava et al (2001) did not find the variant in 90 controls whose ethnicity is unknown. The testing lab did not detect the variant in 200 individuals of either Caucasian or African American descent.

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